Process for the preparation of n-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxo-3,5-dihydro-1,4-benzothiazepin-4-yl)-6-methyl-quinazolin-4-amine

ABSTRACT

The present invention relates to a novel process for the preparation of a compound of the formula (I): 
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable acid addition salts thereof, which is useful for prophylaxis and treatment of respiratory syncytial virus (RSV) infection in mammal or human being.

RELATED APPLICATIONS

This application is a continuation of International ApplicationPCT/EP2015/051066, having an international filing date of Jan. 21, 2015,and which claims benefit under 35 U.S.C §119 to PCT/CN2014/071331 havingan international filing date of Jan. 24, 2014. The entire contents ofthese applications are hereby incorporated herein by reference.

The present invention relates to a process for the preparation of acompound of the formula (I):

and pharmaceutically acceptable addition salts thereof, which is usefulfor prophylaxis and treatment of respiratory syncytial virus (RSV)infection in mammal or human being.

Another aspect of the present invention relates to a novel process forthe preparation of a compound of the formula (V):

wherein R is C₁₋₆alkyl, C₁₋₆alkoxyphenyl-C_(x)H_(2x)— orphenyl-C_(x)H_(2x)—. Compound of the formula (V) is importantintermediate in the synthesis and manufacture of pharmaceutically activecompound of formula (I) as described in patent as described in patentWO2013020993 A1.

BACKGROUND OF THE INVENTION

The patent WO2013020993 A1 disclosed synthetic approaches to obtaincompound of formula (I). However, according to the synthetic approach inpatent WO2013020993 A1, deprotection of one of the intermediates,3-(aminomethyl)-N,N-dibenzyl-oxetan-3-amine, for synthesizing compoundof formula (I) by hydrogenation with palladium on carbon will lead toheavy metal residual issue, which is not suitable for process chemistryand large scale manufacture. In addition, another intermediate,tert-butyl [(3-aminooxetan-3-yl)methyl]carbamate, for synthesizingcompound of formula (I) suffers from instability as the primary amine.

In this invention, a simple and effective synthetic approach isdeveloped to synthesize compounds of formula (I). This syntheticapproach can be applied on technical scale and allows to obtain theproduct in a good yield, desired purity and stable form without usingheavy metal catalyst.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, the term “C₁₋₆alkyl” signifies a saturated, linear- orbranched chain alkyl group containing 1 to 6, particularly 1 to 5 carbonatoms, for example as methyl, ethyl, n-propyl, isopropyl, n-butyl,s-butyl, isobutyl, tert-butyl, n-pentyl, 3-methylbutyl,1,1-dimethylpropyl, n-hexyl, 2-ethylbutyl and the like. Particular“C₁₋₆alkyl” groups are tert-butyl and 1,1-dimethylpropyl.

The term “C_(x)H_(2x)” signifies a saturated, linear- or branched chainalkyl group containing 1 to 6, particularly 1 to 4 carbon atoms.

The term “C₁₋₆alkoxy” signifies a group C₁₋₆alkyl-O—, wherein the“C₁₋₆alkyl” is as defined above, for example methoxy, ethoxy, propoxy,iso-propoxy, n-butoxy, iso-butoxy, 2-butoxy, tert-butoxy and the like.Particular “C₁₋₆alkoxy” groups are methoxy and ethoxy and moreparticularly methoxy.

The term “C₁₋₆alkoxyphenyl” signifies a phenyl substituted by C₁₋₆alkoxygroup as defined above at ortho, meta or para position. Particular“C₁₋₆alkoxyphenyl” group is 4-methoxyphenyl.

The term “amino” refers to primary (—NH₂), secondary (—NH—) or tertiaryamino

The term “hydroxy” refers to the group —OH.

The term “HA” refers to organic or inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid,L-tartaric acid, citric acid, L-lactic acid, maleic acid, fumaric acid,succinic acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid,p-toluenesulfonic acid, oxalic acid, p-nitrobenzoic acid, salicylic acidand 4-chlorobenzoic acid and the like.

The term “acid addition salt” refers to conventional acid addition saltsthat are formed from suitable non-toxic organic or inorganic acids. Acidaddition salts include for example those derived from organic orinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, phosphoric acid, acetic acid, L-tartaric acid, citric acid,L-lactic acid, maleic acid, fumaric acid, succinic acid, methanesulfonicacid, benzenesulfonic acid, benzoic acid, p-toluenesulfonic acid, oxalicacid, p-nitrobenzoic acid, salicylic acid and 4-chlorobenzoic acid andthe like.

TABLE 1 Abbreviations Ac₂O: acetic anhydride AcOH: acetic acid CD3Cl-d3:deuterated chloroform DCM: Dichloromethane DMF: DimethylformamideDMSO-d6: deuterated dimethylsulfoxide DPPA: diphenylphosphoryl azideEtOAC: ethyl acetate EtOH: Ethanol HPLC: high performance liquidchromatography hr or hrs: hour or hours Hz: Hertz kg: Kilogram L: LiterMETHANOL-d4: deuterated methanol MHz: Megahertz mins: Minutes mmol:Millimole MS (ESI): mass spectroscopy (electron spray ionization) MTBE:methyl tert-butyl ether NaOH: sodium hydroxide NMM: 4-methylmorpholineNMR: nuclear magnetic resonance obsd.: Observed sat. Saturated TEA:Triethylamine TEMPO: 2,2,6,6-tetramethylpiperidinooxy TFA:trifluoroacetic acid THF: Tetrahydrofuran

The problems in WO2013020993 A1 are solved according to presentinvention by a process for preparing the compounds of formula (I) shownin scheme 1:

wherein R is C₁₋₆alkyl, C₁₋₆alkoxyphenyl-C_(x)H_(2x)— orphenyl-C_(x)H_(2x)—.

The invention relates to a process for the preparation of a compound ofthe formula (I):

and pharmaceutically acceptable addition salts thereof,comprising the following steps:step a) oxidation of [3-(bromomethyl)oxetan-3-yl]methanol of formula(II) to form a compound of formula (III),

step b) conversion of carboxy group of a compound of formula (III) tocarbamate to form a compound of formula (IV)

wherein R is C₁₋₆alkyl, C₁₋₆alkoxyphenyl-C_(x)H_(2x)— orphenyl-C_(x)H_(2x)—;step c) amination of a compound of formula (IV) to form a compound offormula (V)

wherein R is as defined above;step d) salt formation of a compound of formula (V) with an acid to forma compound of formula (VI)

wherein R is as defined above;step e) substitution reaction of a compound of formula (VI) with acompound of formula (IX) to give a compound of formula (VII)

wherein R is as defined above;step f) substitution reaction of a compound of formula (VII) with acompound of formula (X) to give a compound of formula (VIII)

wherein R is as defined above;step g) comprises deprotection of a compound of formula (VIII) to give acompound of formula (I)

and if necessary, form a pharmaceutically acceptable addition salt.

The synthesis process steps (a), (b) and (c) result in compound offormula (V) which is a novel and is another important aspect of thepresent invention.

A detailed description of present invention of process steps is asfollowing:

step a) comprises preparation of carboxylic acid of formula (III) byoxidizing [3-(bromomethyl)oxetan-3-yl]methanol of formula (II)

This reaction is performed with an oxidant at a reaction temperaturerange between 0° C. and 100° C., particularly between 15° C. to 25° C.The order of addition of reactants can be compelled by convenience.

The reaction can be conducted in various solvents, in particular, thereaction solvent is water, acetonitrile, dichloromethane, ethyl acetateor isopropyl acetate; or a co-solvent which is a mixture of two or morekinds of solvents selected from water, acetonitrile, dichloromethane,ethyl acetate and isopropyl acetate. More particular solvent is aco-solvent of water and acetonitrile.

The oxidant used in this reaction is sodium hypochlorite, potassiumpermanganate, 2,2,6,6-tetramethylpiperidinooxy or pyridiniumchlorochromate; or a co-oxidant which is a mixture of two or more kindsof oxidants selected from sodium hypochlorite, potassium permanganate,2,2,6,6-tetramethylpiperidinooxy and pyridinium chlorochromate.Particular oxidant is a co-oxidant of 2,2,6,6-tetramethylpiperidinooxyand sodium hypochlorite. The oxidation reaction is as a rule finishedafter 1 to 24 hours, particularly 4 to 6 hours.

step b) comprises the conversion of carboxylic acid of formula (III) tocarbamate of formula (IV) through Curtius rearrangement.

The reaction is performed with an azide reagent and a base in an organicsolvent and followed by adding an alcohol at temperature range of 0° C.and 100° C., particularly 80° C.

In this step, a compound of formula (III) is mixed with an azidereagent, particularly diphenylphosphoryl azide, and a base in an organicsolvent to form an active intermediate3-(bromomethyl)-3-isocyanato-oxetane, which can be further converted tocarbamates of formula (IV) by adding various alcohols.

The base used in this reaction is triethylamine, diisopropylethylamineor 4-methyl morpholine, more particularly 4-methyl morpholine.

The reaction can be conducted in many organic solvents. In particular,the solvent used in step b) is acetonitrile, toluene, chlorobenzene,dichloromethane. More particular solvent is toluene.

The reaction temperature lies in the range of 0° C. and 100° C.,particularly 80° C.

Typically, the alcohol used in step b) is tert-butanol,2-methyl-2-butanol, benzyl alcohol or 4-methoxyphenylmethanol,particularly 4-methoxyphenylmethanol.

step c) comprises amination of compound of formula (IV) to form an aminocompound of formula (V).

The reaction is performed with an amination agent, at reactiontemperature range of 0° C. and 60° C., particularly in the rage of 25°C. and 30° C.

In order to form a primary amine, compound of formula (IV) and anamination reagent, particularly liquid ammonia, are charged to anautoclave to give the compound of formula (V).

Reaction temperature as a rule lies in the range of 0° C. and 60° C.,particularly in the rage of 25° C. and 30° C.

The reaction is generally finished after 1 to 24 hours, particularly 8hours.

step d) comprises salt formation of a compound of formula (V) with anacid to form a compound of formula (VI).

The acid used in this reaction includes various organic and inorganicacids, such as hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, acetic acid, L-tartaric acid, citric acid, L-lacticacid, maleic acid, fumaric acid, succinic acid, methanesulfonic acid,benzenesulfonic acid, benzoic acid, p-toluenesulfonic acid, oxalic acid,p-nitrobenzoic acid, salicylic acid and 4-chlorobenzoic acid and thelike, more particularly 4-chlorobenzoic acid.

step e) comprises the substitution reaction of a compound of formula(VI) with a compound of formula (IX) to give a compound of formula(VII).

The reaction can be performed in an organic solvent. In particular, thereaction is performed in tetrahydrofuran, 2-methyltetrahydrofuran oracetonitrile, more particularly in tetrahydrofuran.

The particular reaction temperature range is between 10° C. and 30° C.

step f) comprises the substitution reaction of a compound of formula(VII) with a compound of formula (X) to give a compound of formula(VIII). This reaction is performed in an organic solvent with an acidcatalyst in temperature range between 0° C. and 100° C., particularlybetween 60° C. and 80° C.

The reaction is performed in an organic solvent. In particular, thereaction is performed in tetrahydrofuran, 2-methyltetrahydrofuran,acetonitrile, toluene, methanol, ethanol or iso-propanol, moreparticularly in ethanol.

Acid catalyst used in the reaction is hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, methanesulfonic acid or ammoniumchloride, particularly is ammonium chloride.

step g) comprises the deprotection of a compound of formula (VIII) togive a compound of formula (I). The reaction is performed in an organicsolvent with acid in temperature range between 0° C. and 100° C.,particularly between 10° C. and 40° C.

The organic solvent used in the reaction is dichloromethane,ethylacetate, isopropyl acetate, tetrahydrofuran or dioxane,particularly dichloromethane.

The acid used in the reaction is hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, methanesulfonic acid or trifluoroaceticacid, particularly is or trifluoroacetic acid.

The invention is illustrated further by the following examples that arenot be construed as limiting the invention in scope to the specificprocedures described herein.

This invention further relates to a compound of formula (V):

wherein R is C₁₋₆alkyl, C₁₋₆alkoxyphenyl-C_(x)H_(2x)— orphenyl-C_(x)H_(2x)—.

This invention is also relates to a compound of formula (III):

EXAMPLES Example 1 Preparation of 3-(bromomethyl)oxetane-3-carboxylicacid

To a 100 ml flask was charged [3-(bromomethyl)oxetan-3-yl]methanol (17.3g, 9.6 mmol) followed with 25 ml water and 5.3 mL of acetonitrile andTEMPO (153 mg, 0.96 mmol). The mixture was cooled to 10° C. 15.3 gsodium hypochloride (14%) was added over 10 min with the innertemperature maintained between 15° C. and 20° C. The reaction wasstirred at room temperature till [3-(bromomethyl)oxetan-3-yl]methanolwas consumed as monitored by HPLC. The resulted mixture was adjusted topH 8-9 and extracted with 20 mL EtOAc twice. The aqueous layer wasadjusted to pH 1-2 with 5N aqueous H₂SO₄ solution and extracted withdichloromethane. After removal of dichloromethane,3-(bromomethyl)oxetane-3-carboxylic acid was obtained. MS obsd. (ESI⁺)[(M+H)⁺] 194. 1H NMR (400 MHz, METHANOL-d4) d ppm, 9.40-9.90 (s, 1H),5.00-5.02 (d, J=6.8 Hz, 2H), 4.56-4.57 (d, J=6.8 Hz, 2H), 3.97 (s, 2H)

Example 2 Preparation of (4-methoxyphenyl)methylN-[3-(bromomethyl)oxetan-3-yl]carbamate

To a Reactor 1 was charged 3-(bromomethyl)oxetane-3-carboxylic acid (1.2kg, 6.15 mol) followed by 6.4 kg toluene. The reaction mixture wascooled to 5° C. Then NMM (0.72 kg, 7.12 mol) was added to this reactionmixture slowly. After the addition, the solution was stirred 10 mins atroom temperature.

To Reactor 2 was charged diphenylphosphoryl azide (1.76 kg, 6.39 mol)followed by 3.2 kg toluene. The mixture was heated to 80° C. Solution inReactor 1 was added to Reactor 2 dropwise. After the addition, thereaction mixture was stirred for 30 mins at 80° C. To the reactionmixture was then added 4-methoxyphenylmethanol (0.82 kg, 5.94 mol) in1.58 kg toluene solution slowly. After the addition, the reactionmixture was allowed to hold for 75 mins at 80° C. The reaction wasmonitored using HPLC. After reaction completion, the mixture was cooledto room temperature, and was washed with 6.0 kg water, 6.24 kg 4% sodiumcarbonate aqueous solution and 3.0 kg water sequentially. The organicphase was concentrated till dryness under reduced pressure and theresidue was recrystallized in n-heptane/ethanol. The suspension wasseparated via centrifuge and the wet cake was washed with 1 kgn-heptane. The wet cake was dried under vacuum oven for 24 hours toafford title compound 1.46 kg, yield 72%. MS obsd. (ESI⁺) [(M+H)⁺] 330.1H NMR (400 MHz, CD3Cl-d3) d ppm 7.30-7.33 (d, J=8.4 Hz, 2H), 6.91-6.93(d, J=8.4 Hz, 2H), 5.33 (s, 1H), 5.06 (s, 2H), 4.70-4.72 (d, J=6.4 Hz,2H), 4.51-4.53 (d, J=6.4 Hz, 2H), 4.00 (s, 2H), 3.84 (s, 3H).

Example 3 Preparation of tert-butylN-[3-(bromomethyl)oxetan-3-yl]carbamate

To a 50 ml flask was charged 3-(bromomethyl)oxetane-3-carboxylic acid(2.0 g, 10.3 mmol) followed by 20 mL of anhydrous t-butanol. Thereaction mixture was cooled to 5° C. Then TEA (1.1 g, 11.3 mmol) wasadded. After the addition, DPPA (3.1 g, 10.8 mmol) was added inportions. The mixture was refluxed overnight. The organic phase was thenconcentrated till dryness under reduced pressure and the residue wasdissolved in 30 ml EtOAc. The organic phase was washed with 10 mL Na₂CO₃solution and 10 mL brine. After removal of solvents, tert-butylN-[3-(bromomethyl)oxetan-3-yl]carbamate was obtained.

Example 4 Preparation of benzyl N-[3-(bromomethyl)oxetan-3-yl]carbamate

To a 100 ml flask was charged 3-(bromomethyl)oxetane-3-carboxylic acid(5.0 g, 25.6 mmol) followed by 50 mL of anhydrous toluene. Then TEA(2.87 g, 28.2 mmol) was added. After the addition of TEA, DPPA (7.64 g,26.9 mmol) was added in portions. The mixture was heated at 65° C.-70°C. for 1 hour. To the reaction mixture was then added benzyl alcohol(4.2 g, 38.4 mmol) and heated at 80° C. for 2 hrs. The resulted mixturewas cooled to room temperature and diluted with 50 ml EtOAc. Thereaction mixture was washed with 30 mL water, 30 mL 10% Na₂CO₃ aqueoussolution and 30 mL brine. The organic phase was concentrated to removemost of solvents under reduced pressure and 15 mL heptane was added. Thesuspension was stirred at room temperature for 2 hours and was separatedby filtration. The wet cake was dried under vacuum oven to afford 4.95 gbenzyl N-[3-(bromomethyl)oxetan-3-yl]carbamate.

Example 5 Preparation of 1,1-dimethylpropylN-[3-(bromomethyl)oxetan-3-yl]carbamate

To a 250 ml flask was charged 3-(bromomethyl)oxetane-3-carboxylic acid(20.4 g, 100 mmol) followed by 120 mL of anhydrous toluene. NMM (12.1 g,120 mmol) was added over 10 min. After the addition, DPPA (30.3 g, 110mmol) in 80 ml toluene was added over 30 min. The mixture was heated at80° C.-85° C. for 40 min. To the reaction mixture was then added t-amylalcohol (44 g, 150 mmol) and heated at 80° C. for 3 hrs. The resultedmixture was cooled to room temperature and was washed with 100 mL water,30 mL 10% Na₂CO₃ aqueous solution and 30 mL brine. The organic phase wasconcentrated in vacuum and the crude product was purified by flashchromatography. The product was slurried in heptane. After filtrationand drying, 12.3 g 1,1-dimethylpropylN-[3-(bromomethyl)oxetan-3-yl]carbamate was obtained.

Example 6 Preparation of (4-methoxyphenyl)methylN-[3-(bromomethyl)oxetan-3-yl]carbamate

To a 10 L autoclave was charged (4-methoxyphenyl)methylN-[3-(bromomethyl)oxetan-3-yl]carbamate (1.1 kg, 3.33 mol) and 5.5 Lliquid ammonia. The reaction mixture was stirred at 25° C.-30° C. for 8hours. Then the ammonia was released carefully. To the residue was added5.5 L 2-methyltetrahydrofuran. The mixture was transferred into aseparation funnel. To the mixture was then added 1.1 L 3N NaOH solution.The aqueous phase was extracted with 4.4 L 2-methyltetrahydrofuran. Thecombined organic phase was washed with 1.1 L saturated NaCl aqueoussolution twice. After phase separation, organic phase was concentratedunder vacuum to about 1 L. The crude residual was used directly withoutfurther purification.

Example 7 Preparation of (4-methoxyphenyl)methylN-[3-(bromomethyl)oxetan-3-yl]carbamate

The titled compound is prepared in analogy to Example 6 by using benzylN-[3-(bromomethyl) oxetan-3-yl]carbamate, which is prepared in Example4, instead of (4-methoxyphenyl)methylN-[3-(bromomethyl)oxetan-3-yl]carbamate,

Example 8 Preparation of 1,1-dimethylpropylN-[3-(aminomethyl)oxetan-3-yl]carbamate

The titled compound is prepared in analogy to Example 6 by using1,1-dimethylpropyl N-[3-(bromomethyl)oxetan-3-yl]carbamate, which isprepared in Example 5, instead of (4-methoxyphenyl)methylN-[3-(bromomethyl)oxetan-3-yl]carbamate.

Example 9 Preparation of tert-butylN-[3-(aminomethyl)oxetan-3-yl]carbamate

The titled compound is prepared in analogy to Example 6 by usingtert-butyl N-[3-(bromomethyl)oxetan-3-yl]carbamate, which is prepared inExample 3, instead of (4-methoxyphenyl)methylN-[3-(bromomethyl)oxetan-3-yl]carbamate.

Example 10 Preparation of (4-methoxyphenyl)methylN-[3-(bromomethyl)oxetan-3-yl]carbamate 4-chlorobenzoic acid salt

To the residue from Example 6 was then added 4-chlorobenzoic acid (420g, 2.68 mol) and 2 L MTBE. The mixture was stirred at 15° C.-25° C. for14 hours. Vacuum filtration to collect the solid and the wet cake waswashed with 1 L MTBE. The wet cake was dried under vacuum oven for 24hours to afford 0.81 kg desired salt with yield 57.5%. MS obsd. (ESI⁺)[(M+H)⁺] 423. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.32 (s, 1H), 7.88-7.91(d, J=8.4 Hz, 2H), 7.42-7.45 (d, J=8.4 Hz, 2H), 7.29-7.31 (d, J=8.4 Hz,2H), 6.90-6.92 (d, J=8.4 Hz, 2H), 4.94 (s, 2H), 4.54-4.56 (d, J=6.4 Hz,2H), 4.44-4.45 (d, J=6.4 Hz, 2H), 3.75 (s, 3H), 3.19 (s, 2H).

Example 11 Preparation of (4-methoxyphenyl)methylN-[3-[[(2-chloro-6-methyl-quinazolin-4-yl)amino]methyl]oxetan-3-yl]carbamate

To a 250 L glass-lined reactor was charged (4-methoxyphenyl)methylN-[3-(bromomethyl)oxetan-3-yl]carbamate 4-chlorobenzoic acid salt (8.1kg, 19.2 mol) and 61.6 kg tetrahydrofuran. To the solution was thenadded TEA (5.9 kg, 58.3 mol). The mixture was then cooled to 10° C.-15°C. To the mixture was then added 2,4-dichloro-6-methyl-quinazoline (3.99kg, 18.7 mol) while control reaction temperature at 10° C.-30° C. Thereaction mixture was then stirred at 22° C.-27° C. for 20 hours. HPLCwas used to monitor the reaction. After reaction completion, thereaction mixture was concentrated in vacuum below 40° C. to 24.3-32.4 Lover 3.5 hours while maintaining the bath temperature at 15° C.-25° C.To the residue was then added 80.2 kg water over 100 mins. The mixturewas stirred at 15° C.-25° C. for 3.5 hours. The suspension was separatedusing centrifuge and washed with 48 kg water in four portions over 50mins to afford 23.6 kg wet (4-methoxyphenyl)methylN-[3-[[(2-chloro-6-methyl-quinazolin-4-yl)amino]methyl]oxetan-3-yl]carbamate.

To a 250 L glass-lined reactor was charged 23.6 kg wet(4-methoxyphenyl)methylN-[3-[[(2-chloro-6-methyl-quinazolin-4-yl)amino]methyl]oxetan-3-yl]carbamate,24.0 kg MTBE and 7.0 kg ethylacetate. The mixture was stirred at 15°C.-25° C. for 2.5 hours. The suspension was separated via centrifuge andwashed with 6.0 kg MTBE. The wet cake was dried under vacuum oven at 38°C.-42° C. with a nitrogen bleed for 3 hours and then 40° C.-52° C. for17 hours to afford 7.9 kg title compound with yield 92%. MS obsd. (ESI⁺)[(M+H)⁺] 443. 1H-NMR (400 Hz, DMSO-d6) d ppm 8.67-8.69 (t, J=5.6 Hz,1H), 8.09 (s, 1H), 7.85 (s, 1H), 7.64-7.67 (m, 1H), 7.53-7.55 (m, 1H),7.26-7.29 (d, J=8.4 Hz, 2H), 6.88-6.90 (d, J=8.4 Hz, 2H), 4.96 (s, 2H),4.62-4.64 (d, J=6.4 Hz, 2H), 4.51-4.53 (d, J=6.4 Hz, 2H), 4.07-4.09 (d,J=6.4 Hz, 2H), 3.74 (s, 3H), 2.47 (s, 3H).

Example 12 Preparation of (4-methoxyphenyl)methylN-[3-[[[2-(1,1-dioxo-3,5-dihydro-1,4-benzothiazepin-4-yl)-6-methyl-quinazolin-4-yl]amino]methyl]oxetan-3-yl]carbamatePreparation of intermediate formula (X):2,3,4,5-Tetrahydro-1,4-benzothiazepine-1,1-dioxide

Step 1: Preparation of 2-phenylsulfanylethanamine

To a reactor was charged 56.1 kg of water followed by NaOH (7.0 kg, 175mol). Start the mechanical stirrer until all NaOH dissolved to form asolution. Cool the solution to 25° C. and to the solution was addedsodium thiophenoxide (50.7 kg, aqueous solution) and 2-chloroethylaminehydrochloride (17.7 kg, 153 mol). The mixture was stirred at 25° C. for15 hours. HPLC was used to monitor the reaction. After reactioncompletion, the reaction mixture was extracted with 61.1 kg EtOAc twice.The combined organic phase was concentrated to about 92 L and used innext step without further purification.

Step 2: Preparation of N-(2-phenyl sulfanylethyl)acetamide

The residue of last step was heated to 45° C. and to the solution wasslowly added AcOH (14.0 kg, 233 mol) while control the reactiontemperature below 60° C. The reaction was monitored by HPLC. Afterreaction completion, the solution was cooled to 45° C. and concentratedunder vacuum to remove 55 L EtOAc. The mixture was then cooled to below25° C. and to the solution was slowly added 62.0 kg n-heptane. Afteraddition, the suspension was cooled to 0° C. and held for 1 hour. Thesolid was collected by centrifuge.

The wet cake was dried under vacuum oven for 22 hours to afford 22.2 kgof N-(2-phenylsulfanylethyl) acetamide with 74% yield. MS obsd. (ESI⁺)[(M+H)⁺] 196. 1H-NMR (400 Hz, DMSO-d6) d ppm 8.07 (s, 1H), 7.18-7.40 (m,5H), 3.21-3.26 (m, 2H), 2.99-3.03 (m, 2H), 1.80 (s, 3H).

Step 3: Preparation of1-(3,5-dihydro-2H-1,4-benzothiazepin-4-yl)ethanone

To a reactor was charged N-(2-phenylsulfanylethyl) acetamide (22.2 kg,114 mol) and 124.7 kg toluene. To the solution was then addedparaformaldehyde (2.1 kg, 70 mol), methylsulfonic acid (10.9 kg, 113mol) and Ac₂O (14.0 kg, 137 mol). The reaction mixture was heated to 75°C.-80 and to the reactor was then charged paraformaldehyde (4.9 kg, 163mol) portionwise while control reaction temperature lower than 80° C.After the addition, the reaction mixture was heated to 100° C.-105° C.and held for 1 hour. The reaction was monitored by HPLC. After reactioncompletion, the reaction mixture was cooled to 30° C. and to the reactorwas added 71.1 kg water. Phase separation and the organic solution waswashed with 63.1 kg saturated NaHCO₃ aqueous solution followed by 63.1kg brine solution. The organic phase was then concentrated under vacuumto remove all the organic solvent and the residue was used directly fornext step without further purification.

Step 4: Preparation of1-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone

To the left residue of last step was added 112.8 kg formic acid and 12.8kg water. The mixture was cooled to 0° C. To the reaction mixture wasslowly added 80.4 kg H₂O₂ (35%) while control reaction temperature lowerthan 10° C. After addition, the reaction mixture was stirred for 1 hourat 10° C. Then the reaction mixture was raised to 25° C. and stirred for3 hours. The reaction was monitored using HPLC. After reactioncompletion, to the reaction mixture was added 177.3 kg water and 235.1kg DCM. Phase separation and the aqueous layer was extracted with 165.9kg DCM again. The combined organic phase was washed with 112.7 kg sat.Na₂SO₃ aqueous solution, 112.1 kg sat. Na₂CO₃ aqueous solution and 103.0kg sat. NaCl aqueous solution. The organic phase was then concentratedunder vacuum to remove all the organic solvent. The residue was thendispersed in 54.3 kg EtOH and stirred for 1 hour at 55° C.-65° C. Thesuspension was separated by centrifuge and the wet cake was dried undervacuum oven for 12 hours to afford 17.4 kg1-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone withyield 64%. MS obsd. (ESI⁺) [(M+H)⁺] 240. 1H-NMR (400 Hz, DMSO-d6) d ppm7.92-8.00 (m, 1H), 7.55-7.74 (m, 3H), 4.60-4.88 (m, 2H), 4.05 (brs, 2H),3.48-3.70 (m, 2H), 3.53 (d, J=8.0 Hz, 3H).

Step 5: Preparation of2,3,4,5-tetrahydro-1,4-benzothiazepine-1,1-dioxide

To a reactor was charged1-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone (16.6kg, 69.4 mol), 55.2 kg EtOH and 55. 8 kg NaOH aqueous solution (11.1 kgNaOH in 44.7 kg H₂O). The reaction mixture was heated to 74-79° C. andheld for 24 hours at this temperature. The reaction was monitored usingHPLC. After reaction completion, the mixture was cooled to 50° C.-55° C.and the organic solvent was removed under reduced pressure. To thereactor was then added 104.1 kg water and the mixture was cooled to 0°C.-7° C. and held for 1 hour. The suspension was separated usingcentrifuge and the wet cake was washed with 44.7 kg water twice. The wetcake was dried under vacuum oven for 24 hours to afford 9.9 kg2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide with 72.3% yield. MSobsd. (ESI⁺) [(M+H)⁺] 198. 1H-NMR (400 Hz, DMSO-d6) d ppm 7.89 (dd,J=1.2, 7.6 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.42(d, J=7.6 Hz, 1H), 4.04 (s, 2H), 3.30-3.32 (m, 2H), 3.25-3.30 (m, 2H),2.64 (s, 1H).

Preparation of (4-methoxyphenyl) methylN-[3-[[[2-(1,1-dioxo-3,5-dihydro-1,4-benzothiazepin-4-yl)-6-methyl-quinazolin-4-yl]amino]methyl]oxetan-3-yl]carbamate

To a 250 L glass-lined reactor was charged 63 kg EtOH followed by(4-methoxyphenyl)methylN-[3-[[(2-chloro-6-methyl-quinazolin-4-yl)amino]methyl]oxetan-3-yl]carbamate(7.8 kg, 17.6 mol), 2,3,4,5-tetrahydro-1,4-benzothiazepine-1,1-dioxide(3.89 kg, 19.7 mol) and ammonium chloride (49 g, 0.92 mol). The reactionmixture was stirred at 68° C.-72° C. for 20 hours. HPLC was used tomonitor the reaction. After reaction completion, the reaction mixturewas slowly cooled to 20° C.-25° C. The solids were collected by vacuumfiltration and washed with 15.6 kg EtOH in two portions. The wet cakewas dried in a vacuum oven with a nitrogen bleed at 38° C.-42° C. forabout 4 hours and then heated to 50° C.-55° C. for 30 hours to afford11.0 kg title compound with yield 88%. MS obsd. (ESI⁺) [(M+H)⁺] 604.1H-NMR (400 Hz, DMSO) d ppm 9.57 (s, 1H), 8.14 (s, 1H), 7.93-7.95 (d,1H, J=8), 7.68 (m, 3H), 7.57-7.58 (m, 1H), 7.22-7.23 (d, 2H, J=4),7.68-7.69 (d, 2H, J=4), 4.98-5.17 (m, 2H), 4.26-4.68 (m, 5H), 3.74-4.1(m, 3H), 3.4-3.46 (t, 1H, J=8), 2.51 (s, 3H), 2.39 (s, 3H).

Example 13 Preparation of N-[(3-aminooxetan-3-yl)methyl]-2-(1,1-dioxo-3,5-dihydro-1,4-benzothiazepin-4-yl)-6-methyl-quinazolin-4-amine

To a 250 L glass-lined reactor was chargedN-[3-[[[2-(1,1-dioxo-3,5-dihydro-1,4-benzothiazepin-4-yl)-6-methyl-quinazolin-4-yl]amino]methyl]oxetan-3-yl]carbamate(10.8 kg, 24.6 mol) and 120 kg dichloromethane. To the mixture was thenadded 16.0 kg 1N NaOH solution in portions. After phase separation, theaqueous phase was extracted with 14.0 kg dichloromethane. The combinedorganic phase was washed with 25 kg 20% NaCl aqueous solution, then wastransferred to a 100 L glass-lined reactor and concentrated to 30-35 Lbelow 35° C. in vacuum to prepare Solution 1.

To another 250 L glass-lined reactor were charged with 26.0 kgdichloromethane and 16.0 kg trifluoroacetic acid. The mixture was cooledto 15° C.-20° C. and to the solution was added the titled Solution 1 inportions. The mixture was stirred for 30 mins at 15° C.-25° C. and thencooled to 0° C.-10° C. To the mixture was added 39.8 kg DMF and then thesolution was concentrated to 62-65 L between 15° C.-30° C. in vacuum forover 16.5 hours to afford Solution 2.

To a 300 L glass-lined reactor was charged 128.3 kg 1.5N NaOH solutionand cooled to 5° C.-7° C. To the reactor was then added 3.0 kgdimethylformamide followed by Solution 2. The suspension was stirred at7° C.-11° C. for 30 mins. The solid was collected by vacuum filtrationand washed with 101 kg water. Then the wet solid was charged into a 250L glass-lined reactor followed by 54.0 kg EtOH. The mixture was heatedto 74° C.-78° C. and stirred for 4.5 hours. The mixture was then cooledto 20° C.-25° C. The solid was collected by vacuum filtration and thewet cake was washed with 15.0 kg EtOH. The wet cake was dried in vacuumoven at 48° C.-52° C. with nitrogen bleed for 20 hours to afford 5.82 kgtitle compound with yield 85%. MS obsd. (ESI⁺) [(M+H)⁺] 440. 1H-NMR (400Hz, METHANOL-D4) d ppm 7.98 (d, J=7.6 Hz, 1H), 7.86 (d, J=7.6 Hz, 1H),7.73 (s, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.32-7.47 (m, 3H), 5.53 (s, 2H),4.58 (brs, 2H), 3.84 (s, 2H), 3.53 (t, J=4.8 Hz, 2H), 2.41 (2, 3H), 2.21(m, 2H), 1.97-2.04 (m, 2H), 1.82-1.91 (m, 2H).

1. Process for the preparation of a compound of the formula (I):

and pharmaceutically acceptable addition salts thereof, comprising thefollowing steps: step a) oxidation of[3-(bromomethyl)oxetan-3-yl]methanol of formula (II) to form a compoundof formula (III)

step b) conversion of carboxy group of a compound of formula (III) tocarbamate to form a compound of formula (IV)

wherein R is C₁₋₆alkyl, C₁₋₆alkoxyphenyl-C_(x)H_(2x)— orphenyl-C_(x)H_(2x)—; step c) amination of a compound of formula (IV) toform a compound of formula (V)

wherein R is as defined above; step d) salt formation of a compound offormula (V) with an acid to form a compound of formula (VI)

wherein R is as defined above; step e) substitution reaction of acompound of formula (VI) with a compound of formula (IX) to give acompound of formula (VII)

wherein R is as defined above; step f) substitution reaction of acompound of formula (VII) with a compound of formula (X) to give acompound of formula (VIII)

wherein R is as defined above; step g) comprises deprotection of acompound of formula (VIII) to give a compound of formula (I)

and if necessary, form a pharmaceutically acceptable addition salt. 2.Process for the preparation of a compound of the formula (V):

wherein R is C₁₋₆alkyl, C₁₋₆alkoxyphenyl-C_(x)H_(2x)— orphenyl-C_(x)H_(2x)—, comprising the following steps: Step a) Conversionof carboxy group to carbamate to form a compound of formula (III)

Step b) Amination of a compound of formula (III) to form a compound offormula (I)


3. A process according to claim 1, wherein R is tert-butyl,1,1-dimethylpropyl, benzyl or 4-methoxyphenylmethyl.
 4. A processaccording to claim 1, wherein step a) is performed with an oxidant at areaction temperature range between 0° C. and 100° C., particularlybetween 15° C. to 25° C.
 5. A process according to claim 1, wherein stepa) is performed in a solvent selected from water, acetonitrile,dichloromethane, ethyl acetate and isopropyl acetate; or a co-solventwhich is a mixture of two or more kinds of solvents selected from water,acetonitrile, dichloromethane, ethyl acetate and isopropyl acetate. Moreparticular solvent is a co-solvent of water and acetonitrile.
 6. Aprocess according to claim 4, wherein the oxidant is selected fromsodium hypochlorite, potassium permanganate,2,2,6,6-tetramethylpiperidinooxy and pyridinium chlorochromate; or aco-oxidant which is a mixture of two or more kinds of oxidants selectedfrom sodium hypochlorite, potassium permanganate,2,2,6,6-tetramethylpiperidinooxy and pyridinium chlorochromate,particularly the oxidant is a co-oxidant of2,2,6,6-tetramethylpiperidinooxy and sodium hypochlorite.
 7. A processaccording to claim 1, wherein step b) is performed with an azide reagentand a base in an organic solvent and followed by adding an alcohol attemperature range of 0° C. and 100° C., particularly 80° C.
 8. A processaccording to claim 7, wherein the azide reagent used in step b) isdiphenylphosphoryl azide.
 9. A process according to claim 7, wherein thebase used in step b) is triethylamine, diisopropylethylamine or 4-methylmorpholine, more particularly 4-methylmorpholine.
 10. A processaccording to claim 7, wherein the solvent used in step b) isacetonitrile, toluene, chlorobenzene or dichloromethane, moreparticularly is toluene.
 11. A process according to claim 7, wherein thealcohol used in step b) is tert-butanol, 2-methyl-2-butanol, benzylalcohol or 4-methoxyphenylmethanol, more particularly is4-methoxyphenylmethanol.
 12. A process according to claim 1, whereinstep c) is performed with an amination agent, at reaction temperaturerange of 0° C. and 60° C., particularly in the rage of 25° C. and 30° C.13. A process according to claim 12, wherein the amination agent used instep c) is liquid ammonia.
 14. A process according to claim 1, whereinstep d) is performed in a solvent with an organic or inorganic acid at atemperature range of 0° C. and 60° C., particularly in the rage of 15°C. and 25° C.
 15. A process according to claim 14, wherein the solventused in step d) is tetrahydrofuran, 2-methyltetrahydrofuran,acetonitrile, ethylacetate or methyl tert-butyl ether, more particularlyin methyl tert-butyl ether.
 16. A process according to claim 14, whereinthe acid used in step d) is hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, acetic acid, L-tartaric acid, citricacid, L-lactic acid, maleic acid, fumaric acid, succinic acid,methanesulfonic acid, benzenesulfonic acid, benzoic acid,p-toluenesulfonic acid, oxalic acid, p-nitrobenzoic acid, salicylic acidor 4-chlorobenzoic acid, more particularly 4-chlorobenzoic acid.
 17. Aprocess according to claim 1, wherein step e) is performed in an organicsolvent, particularly in tetrahydrofuran at reaction temperature rangebetween 10° C. and 30° C.
 18. A process according to claim 1, whereinstep f) is performed in an organic solvent with acid catalyst intemperature range between 0° C. and 100° C., particularly between 60° C.and 80° C.
 19. A process according to claim 1, wherein step g) isperformed in an organic solvent with acid in temperature range between0° C. and 100° C., particularly between 10° C. and 40° C.
 20. A compoundof formula (V):

wherein R is C₁₋₆alkyl, C₁₋₆alkoxyphenyl-C_(x)H_(2x)— orphenyl-C_(x)H_(2x)—.
 21. A compound of formula (II):